MAO-B inhibitors: multiple roles in the therapy of neurodegenerative disorders?

Abstract

Monoamine oxidases play a central role in catecholamine catabolism in the central nervous system. The biochemical and pharmacological properties of inhibitors of the monoamine oxidase type B are reviewed. The evidence for biochemical activities distinct from their ability to inhibit MAO-B is discussed, including possible antioxidative and antiapoptotic activities of these agents. The significance of these properties for the pharmacological management of Parkinson's disease and the evidence for a neuroprotective effect of one such agent (selegiline) is also discussed.

Introduction

Monoamine oxidase (MAO; amine: oxygen reductase (deaminating, flavin-containing), EC 1.4.3.4) is an integral protein of the outer mitochondrial membrane, and catalyses the following overall oxidative deamination reaction:

$$\text{RCH}{}_2\text{NH}{}_2\text{+H}{}_2\text{O+O}{}_2\text{→RCHO+NH}{}_3\text{+H}{}_2\text{O}{}_2$$

MAO plays a major role in the in vivo inactivation of biogenic and diet-derived amines in both the central nervous system (CNS) and in peripheral neurons and tissues; the most important substrates for the enzyme in the CNS are the catecholamine neurotransmitters (dopamine (DA), adrenaline and noradrenaline (NA)), serotonin (5-hydroxytryptamine; 5HT) and β-phenylethylamine (PE). Two MAO isozymes are distinguished on the basis of their substrate preferences and sensitivity to inhibition by the MAO inhibitor, clorgyline [1]:

• MAO type A (MAO-A), which is selectively and irreversibly inhibited by low concentrations (nM) of clorgyline. In the human CNS, it is chiefly responsible for the deamination of 5HT and NA; in the intestine, it metabolizes the oxidation of tyramine.

• MAO-B, which is relatively insensitive to clorgyline. MAO-B inhibition in the human brain principally reduces the catabolism of DA and PE.

The immunologically distinct isozymes are coded for by separate but closely related genes on the X chromosome [2]. The active sites of the two forms exhibit a 93.9% sequence identity [3]; it is the secondary binding sites of the two molecules and possibly their lipid environment which confer their substrate selectivity ([4], [5], [6]; Table 1). Most relevant for our discussion is the fact that DA in the human brain is a substrate for both MAO-A and -B [7].

It is now recognized that there exist significant differences between the rodent and human brains with respect to the regional and cellular distribution of the two MAO forms, as well as the substrate specificity and sensitivity of the two isozymes (Table 2). In contrast to the rat brain, MAO-B is the major form in the human and guinea pig CNS [8], [9], [10], [11], [12]. Moreover, the rat MAO isozymes are reported to have short half-lives, whereas that of MAO-B in primate brain is at least 30 days [13], [14]. These differences are of critical importance, as rodents have been employed for most laboratory studies; such results can only be extrapolated to the human CNS with caution.

Given the substrate specificity of the two MAO forms, their distribution in the human brain is perhaps surprising: the highest MAO-A concentrations are in the catecholaminergic neurons of the locus ceruleus, and of MAO-B in the serotonergic and histaminergic neurons of the raphe and posterior hypothalamus [12], [15], [16], [17]. There are especially high concentrations of both forms in the human basal ganglia [9]. The DAergic neurons of the substantia nigra (SN) in both rodents and primates express MAO-A, but not MAO-B [15]. Although Westlund et al. [16] identified a dense distribution of MAO-B-immunoreactive nerve terminals in the SN, which contrasted with the weak signal for the striatum, nigral MAO-B is located primarily in glial cells [18], [19]. Richards et al. [20] employed quantitative enzyme autoradiography to identify a three-fold higher level of MAO-B than of MAO-A in the SN; however, the levels of the A-form were higher in the pars compacta than in the reticulata, while the opposite distribution was noted for MAO-B.

The topographic location of the MAO types thus does not coincide with that of their presumed natural substrates, and the role of MAO may principally be to protect the local environment from excess levels of foreign monoamines. MAO-B may indirectly regulate extraneuronal transmitter levels, particularly those of DA, by regulating the levels of a release-promoting substance, such as PE [21]. MAO-A, on the other hand, acts to maintain low intraneuronal concentrations of DA, NA and 5HT.

Important for our discussion is the fact that platelet MAO is principally MAO-B (Table 2). As the only means for assessing MAO inhibition in the CNS of a living subject mitigate against their mass application (for example, positron emission tomography (PET) [22], [23]), inhibition of platelet MAO-B activity is the standard parameter employed for estimation of the effect of a MAO-B inhibitor.

CNS MAO-B (but not MAO-A) activity increases with age in both humans and animals [24], [25], [26], [27], [28], perhaps as a result of the glial cell proliferation associated with neuronal loss. In humans, this increase commences at 50–60 years of age, but is not observed in the SN [29]. Increased MAO-B levels in Alzheimer's plaques have also been reported [29], [30]. Increased blood platelet MAO-B activity has been reported in both Alzheimer's (AD) and Parkinson's diseases (PD), although the increased activity in the latter disorder might be associated with the frequently coexistent AD, rather than directly with PD [31]. Fowler et al. [32] reported that MAO-B activity was reduced by 40% in the brains of smokers; tobacco use is associated both with psychiatric disease and with a reduced risk for PD.